IgE-mediated allergic asthma affects 10 million Americans. An allergic asthma attack is triggered by exposure to allergens that cause bronchoconstriction, which is relieved by the administration of a beta-2-adrenergic receptor ((2AR) agonist to relax smooth muscle cells surrounding the bronchioles. Other cells in the lung express the (2AR, including B lymphocytes that produce IgE. High levels of IgE translate into more severe allergic asthma symptoms. Our laboratory has reported that (2AR stimulation on an activated B cell increases the rate of IgE transcription. The natural ligand for the (2AR is the neurotransmitter norepinephrine, which is also associated with the severity of allergic asthma attacks. If the level of IgE is associated with the severity of an asthmatic response and if (2AR stimulation on a B cell increases IgE, it will be important to identify the mechanism that mediates this increase. IgE levels are regulated by the cleavage of membrane CD23 (mCD23) to soluble CD23 (sCD23), which, respectively, regulate IgE production negatively or positively. Our laboratory determined that there was a (2AR-induced increase in total cytoplasmic CD23 and sCD23, while mCD23 remained constant, suggesting that the mechanism involved in the regulation of mCD23 cleavage may be targeted by signaling intermediates activated after (2AR stimulation on a B cell. The enzymes that cleave mCD23 to sCD23 belong to a family of A Disintegrin And Metalloproteinases (ADAMs), which, when active, function to increase the positive soluble regulator of IgE, while keeping the negative membrane regulator constant. Although ADAM10 is reported to be the primary sheddase, our preliminary data show that the levels of ADAMs 8,10, and 28 increase in a B cell after activation, but that only the levels of ADAMs 8 and 28 increase further after concomitant (2AR stimulation. In experiments outlined in this proposal, we will test the hypothesis that (2AR stimulation on a B cell increases the ratio of sCD23/mCD23 and the subsequent level of IgE produced by regulating either the level and/or proteolytic activity of specific ADAMs. The significance of testing this hypothesis is that the data will elucidate a mechanism by which (2AR stimulation on a B cell participates in regulating the level of IgE, thus identifying novel drug targets in a B cell that would prevent agonist activity to overproduce IgE, without interfering with agonist activity on other cells that would relieve allergic asthma symptoms. PUBLIC HEALTH RELEVANCE: The current treatment for allergic asthma symptoms is to administer a beta-2 adrenergic receptor ((2AR) agonist drug, which binds to the (2AR expressed on bronchiole smooth muscle cells to cause them to relax, thus relieving bronchoconstriction. However, these agonists stimulate the (2AR on other cells, such as B cells to increase the level of IgE produced. Because the level of IgE is associated with the severity of allergic asthma symptoms, it will be important to identify the mechanism by which the 2(AR on a B cell increases IgE and if this mechanism is different from that used to relax bronchiole smooth muscle.